Alzheimer's disease (AD) is the most common form of age-dependent cognitive impairment (BROOKMEYER, et al., Alzheimers Dement, 3(3):186-191 (2007); QIU, et al., Dialogues Clin Neurosci, 11(2):111-128 (2009)). The key neuropathological features of AD include two extracellular protein aggregates: neurofibrillary tangles and amyloid beta (Aβ) plaques (GLENNER, et al., Biochem Biophys Res Commun, 120(3):885-890 (1984); SELKOE, Cold Spring Harb Perspect Biol, 3(7) (2011); TERRY, et al., Ann Neurol, 14(5):497-506 (1983)). AD is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyms. Both amyloid plaques and neurofibrillary tangles found in brains of subjects afflicted with AD.
Although it remains largely unknown how the disease is initiated, the aberrant accumulation of Aβ in brain regions involved in cognitive function is believed to play a causative role in AD development.
Aβ causes significant pathological changes including dysfunction in energy metabolism, oxidative stress and inflammation (DURAN-GONZALEZ, et al., Neurobiol Aging, 34(8):2071-2076 (2013); ONYANGO, et al., Neurobiol Dis, 19(1-2):312-322 (2005)), ultimately resulting in the synaptic dysfunction underlying cognitive impairment (CLEARY, et al., Nat Neurosci, 8(1):79-84 (2005)). Mitochondria have emerged as a central organelle in the pathobiology of AD (ECKERT, et al., Mol Neurobiol, 4(1):136-150 (2012); REDDY, et al., CNS Spectr, 14(8 Suppl 7):8-13, discussion 16-18 (2009)). Mitochondrial defects in AD include increased reactive oxygen species (ROS) production (MANCZAK, et al., Hum Mol Genet, 15(9):1437-1449 (2006)), accumulation of mitochondrial DNA mutations (HOWELL et al. 2005), impairment in energy metabolism (ANANDATHEERTHAVARADA, et al., J Cell Biol, 161(1):41-54 (2003)), reduced mitochondrial respiratory chain complex activity (RHEIN, et al., Proc Natl Acad Sci USA, 106(47):20057-20062 (2009)), deregulation of calcium homeostasis, decreased mitochondrial transport, and imbalanced mitochondrial fission and fusion (WANG, et al., J Neurosci, 29(28):9090-9103 (2009); ZHU, et al., J. Alzheimers Dis, 33(Suppl 1):5253-262 (2013)). Despite the extensive evidence pointing to the role of mitochondria in AD, it has been difficult to prove that mitochondrial therapies are effective in reversing or slowing down AD progression. Mitochondrially-targeted anti-oxidants have been used successfully in AD animal models, but their clinical efficacy remains to be determined. Small molecules, such as MitoQ, could act as ROS scavengers, but do not appear to fundamentally prevent mitochondrial dysfunction or restore damaged mitochondria in AD.
Modulation of mitochondrial proteins involved in mitochondrial structure and function is a novel approach to achieve neuroprotection by counteracting the effects of noxious factors that target the organelles, such as Aβ. Genetic deletion of cyclophilin D (CypD), a regulator of the Ca2+-dependent permeability transition pore (MPTP), in APP mice resulted in improved mitochondrial function, morphology and transport in vitro, reduced Aβ and oxidative stress-induced neuronal cell death, and substantially improved learning and memory and synaptic function in vivo, in an AD mouse model (DU, et al., Nat Med, 14(10):1097-105 (2008)). Unfortunately, CypD is a highly conserved protein that plays an important role in Ca2+ regulation, and its complete deletion may lead to unforeseen consequences on cell function and survival. On the other hand, CypD function cannot be only partially reduced to achieve an effect on MPTP, since even half the amount of the protein is sufficient to produce normal MPTP responses. Therefore, an alternative protein approach is needed to modulate mitochondrial stability in AD.
Prohibitin is an essential mitochondrial protein that has been implicated in a wide variety of functions in many cell types (ZHOU, et al., J Neurosci, 32(2):583-592 (2012)). Prohibitins are assembled into a ring-like structure with 16-20 alternating Phb1 and Phb2 subunits in the inner mitochondrial membrane (MERKWIRTH, et al., PLOS Genetics, 8(11):1-13 (2012)). Prohibitin gene silencing increases the vulnerability of neurons to injury, associated with a loss of mitochondrial membrane potential and an increase mitochondrial production of ROS (ZHOU, et al., J Neurosci, 32(2):583-592 (2012)). Similarly, loss of prohibitin has been shown to lead to tau hyperphosphorylation and neurodegeneration (MERKWIRTH, et al., PLOS Genetics, 8(11):1-13 (2012)). However, the art has not demonstrated the ability of prohibitin to restore cognitive function in subjects showing cognitive dysfunction resulting from a neurological disease.
Disclosed herein are new compositions and gene therapy methods to restore cognitive function in subjects suffering from AD and other neurodegenerative diseases and conditions by increasing the expression of exogenous prohibitin in neurons of the brains of the subjects.